The present invention relates to a method of delivering a bisphosphonate and/or strontium ranelate below the surface of a bone using a mechanical force.
Loss of bone strength near the site of a bone implant or prosthesis is a major factor leading to the eventual failure of such implants and prosthesis. These failures result not only in discomfort for the patients, but often the need for follow-up surgery to replace the failing implant or prosthetic.
Living bone is in constant turnover. Existing bone undergoes resorption and new bone is deposited. In healthy bone, the deposition of new bone matches or exceeds resorption of existing bone. However, when this balance is lost, e.g., due to disease, nutritional deficiency, or tissue damage, the resorption of bone exceeds the deposition of bone and a net loss of bone results.
The loss of bone produces weakening of the bones, as seen in osteoporosis. Such bone loss is common near the site of bone implants and prosthetics. The loss of bone adjacent to an implant or prosthetic contributes to the weakening of the attachment, and eventual failure, of the implant or prosthetic.
The most common treatment for bone loss is the administration of a bisphosphonate. Bisphosphonates preferentially kill or inactivate osteoclast cells. Osteoclast cells break down bone tissue. Conversely, osteoblast cells form bone tissue. Thus, bisphosphonate administration reduces bone resorption without effecting bone formation, in some instances leading to a net increase of bone mass over an untreated state. Bisphosphonates can also be administered with other actives, such as for example, vitamin D.
Systemic administration of bisphosphonates, e.g., orally or intravenously, can lead to side effects. Oral administration can result in upset stomach and severe inflammation and erosion of the esophagus. Administration is also very cumbersome and inconvenient. Intravenous administration can produce fever and flu-like symptoms and, in high doses, has been associated with osteonecrosis of the jaw. Severe bone, muscle, and joint pain have also been reported after systemic bisphosphonate treatment.
In patients who are intolerant or otherwise contraindicated for bisphosphonate treatment systemically, or as a supplement to traditional bisphosphonate treatment, local delivery of a bisphosphonate in conjunction with an implant or prosthesis is an attractive alternative. A number of methods for local delivery of a bisphosphonate have been proposed.
For example, the combination of a bisphosphonate with an apatite coating on an implant that is commonly used in orthopedic implants has been shown (V. A. Stadelmann, et al., Implants delivering bisphosphonate locally increase periprosthetic bone density in and osteoporotic sheep model. A pilot study, European Cells and Materials, 16:10-16 (2008)). Bisphosphonates, however, bind preferentially to calcium salts and their range of influence is limited to a region very close to the bone implant interface, i.e., from 0 to 0.5 millimeters below the surface of the bone. Fibrinogen can be used to bind a bisphosphonate to an implant (Tengvall P, et al., Surface immobilized bisphosphonate improves stainless-steel screw fixation in rats, Biomaterials 25(11): 2133-8 (2004); Aspenberg, P., Bisphosphonates and implants: An overview, Acta Orthopaedica, 80 (1):119-123 (2009)), but the depth of penetration of the bisphosphonate is similarly limited. A bisphosphonate can also be delivered either by painting it onto the bone, or in combination with bone chips. The disadvantage in such cases is that it is impossible to determine where the drug is delivered or the amount delivered to the bone, because the distribution of the drug is impossible to control in either case.
Strontium ranelate is an antiosteoporoitic compound known to both reduce resorption of bone by the osteoclasts and increase bone deposition by osteoblasts. Thus, strontium ranelate produces a rebalancing to bone turnover in favor of formation of bones.